Endoscopic resection for early esophageal cancer has a risk of residual margins. The risk these residual margins pose have not been fully evaluated. The present study aimed to investigate the associated risk factors and prognosis of residual margins following the endoscopic resection of early esophageal squamous cell carcinoma. In total, 369 patients (381 lesions) with early esophageal squamous cell carcinoma treated in the Fourth Hospital of Hebei Medical University (Shijiazhuang, China) with endoscopic resection were retrospectively analyzed. Sex, age, location, tumor diameter, depth of tumor invasion, endoscopic treatment, endoscopic ultrasonography (EUS) before resection, work experience of endoscopists and the degree of tumor differentiation were all evaluated as potential risk factors. In addition, the prognosis of patients with positive margins were analyzed. A total of 73 patients (73/381, 19.2%) had positive margins after endoscopic resection. Amongst the 65 patients who were successfully followed up, five patients succumbed to cardiovascular and cerebrovascular diseases, one patient received radiotherapy, two patients received radiotherapy and chemotherapy whilst one patient received chemotherapy. By contrast, 12 patients received surgery and 20 patients received additional endoscopic mucosal resection or endoscopic submucosal dissection. The other 29 patients were followed up regularly and no recurrence could be found. Univariate analysis revealed that tumor diameter, endoscopic treatment, depth of invasion, EUS before resection, degree of tumor differentiation and direction of invasion were all associated with the positive margin. Multivariate logistic regression analysis then found that EUS before resection, degree of tumor differentiation and depth of tumor invasion are independent risk factors for positive margins after endoscopic resection. These results suggest that poorly differentiated lesions and deeper invasion depth can increase the risk of positive margin after endoscopic resection. As a result, EUS evaluation before resection may reduce the risk of invasion depth. In addition, for poorly differentiated lesions, more aggressive treatment regimens may be recommended for preventing recurrence.
Esophageal cancer is a common type digestive system malignancy and currently ranks sixth in terms of the rate of cancer-associated mortality worldwide (
As advancements in endoscopic technology are made continuously, endoscopic resection is becoming the standard, minimally invasive treatment procedure for early esophageal cancer (
However, similar to traditional esophagectomy, endoscopic resection also has the risk of a positive margin (positive margin refers to the presence of atypical cells at the lateral or deep resection margins). Positive margin after the endoscopic resection of early esophageal carcinoma has direct implications on the choice of treatment and disease prognosis (
Therefore, to explore methods of improving the prognosis of patients after the endoscopic resection of esophageal cancer, the present study investigated the potential risk factors for positive margins by comprehensively analyzing clinical and pathological data.
The present study retrospectively analyzed the clinical, endoscopic and pathological data of patients with esophageal mucosal lesions treated with endoscopic resection in the Fourth Hospital of Hebei Medical University (Shijiazhuang, China) from January 2011 to December 2020.
The inclusion criteria of the lesions were as follows: i) Complete resection of lesions; ii) pathological diagnosis after endoscopic treatment was atypical cells (cells that looked different and function differently than normal) [low-grade intraepithelial neoplasia (LIN), high-grade intraepithelial neoplasia (HIN) or invasive cancer]; and iii) patients provided informed consent. The exclusion criterion was patients who were pathologically diagnosed with adenocarcinoma or inflammation after endoscopic treatment. Of note, intraepithelial neoplasia was defined as the neoplastic change before epithelial invasion, which can be divided further into ‘low-grade’ and ‘high-grade’ according to whether the structural and cytological abnormalities observed occupy the upper part of the epithelium (
A total of 369 patients (381 lesions) received endoscopic resection due to early esophageal carcinoma. Of these, 236 were males and 133 were females with a mean age of 63.5±9.9 years. The main clinical symptoms were retropharyngeal asphyxia and retrosternal pain. No other symptoms or findings could be observed during physical examination. All patients and their relatives were aware of the risks and benefits of endoscopic resection, following which written informed consent was obtained from all participants. The present study was approved by the Ethics committee of the Fourth Hospital of Hebei Medical University (Shijiazhuang, China).
Under the guidance of endoscopy, two treatment methods were used to remove the tumor: Endoscopic mucosal resection (EMR) and ESD.
The type of endoscopic treatment performed in the present study was by professionally trained endoscopists using a single-channel endoscope (Olympus H260; Olympus Corporation). Argon plasma coagulation (APC; APC probes for flexible endoscope; Erbe Elektromedizin GmbH) was used to mark ~5 mm outside the boundary of the lesion. After fully marking the border, an epinephrine-containing hypertonic saline solution was injected into the submucosa for submucosal lifting. A circumferential mucosal incision was then created around the marking spots. In cases where the EMR technique was used, asymmetrical polypectomy snare (MTW Endoskopie) resection was initiated. For ESD, the submucosal layer was dissected using the IT-knife2 (KD-611L; Olympus Corporation). After the lesions were resected, the wounds were closed with APC, hot biopsy forceps coagulation or using titanium clips according to the wound conditions (
The resected specimens were processed and fixed immediately, before the lesion size was measured. After fixation with 10% formalin (20-25˚C for 12-24 h), the specimens were sent for pathological examination. The samples were cut into continuous sections at 2-mm intervals from top to bottom and embedded in paraffin. In total, three sections were prepared from each tissue and then stained with hematoxylin and eosin using the Ventana HE 600 automatic staining machine (Roche Diagnostics; 20-25˚C). An experienced pathologist (Dr Yao Liu, Department of Pathology, Fourth Hospital of Hebei Medical University) then used a light microscope (DM1000; Leica Microsystems GmbH; magnification, x200) to evaluate tumor involvement in the lateral or deep resection margin to avoid misjudgment. When examining the tissue sections for pathological evaluation, all sections were observed from the top of the tissue to identify the nature of the lesion, the degree of tumor differentiation, whether the vertical/transverse edge of the tumor was positive and whether there was vascular infiltration. A positive resection margin as defined as the presence of atypical cells (LIN, HIN or invasive cancer) at the lateral or deep resection margin.
Sex, age, lesion location, tumor diameter, depth of invasion, endoscopic treatment, endoscopic ultrasonography (EUS) before resection, working experience of the endoscopist and degree of tumor differentiation were all analyzed as potential risk factors.
Continuous data are presented as the mean ± standard deviation. χ2 and nonparametric Mann-Whitney U tests were used for statistical analysis. Univariate and multivariate logistic regression models were used to examine the association between the variables and positive margins risk factors. P<0.05 was considered to indicate a statistically significant significance. The SPSS vl9.0 (IBM Corp.) was used for data processing.
The present study was a retrospective analysis of the data collected from 369 patients with early esophageal cancer who met the inclusion criteria. Among all study participants, 236 were male and 133 were female with a ratio of 1.8:1. The average age was 63.5±9.9 (range, 31-85) years.
In total, 73 patients had positive margin, such that the positive rate was 19.2%, where 64 (16.8%) were positive for lateral margins and nine (2.4%) were positive for vertical margins. In addition, it was found that the residual rates of EMR and ESD were 26.9 and 16.7%, respectively. Only 7.5% (23/308) poorly differentiated lesions were diagnosed in negative margins. By contrast, the proportion of positive margin specimens was 28.8% (21/73). There was no vascular invasion or submucosal lymphatic metastasis. After communicating with the patients and their families, 29 patients asked for regular follow-up, while others with positive margins received another ESD or EMR and were followed up 1 month after operation. During the follow-up period, endoscopy was performed 3, 6 and 12 months after endoscopic resection, before being performed every year thereafter. Chest CT was also performed 6 and 12 months after endoscopic resection followed by once a year thereafter as a precaution for distant metastasis. Follow up was halted 5 years after endoscopic resection. If tumor cells were found at the edge of the deep resection, additional esophagectomy or esophageal radiotherapy and chemotherapy would be performed. These treatment options were selected according to the situation of each patient and the wishes of patients and their families. In the present study, 65 cases of residual tumors were successfully followed up for 2-60 months, with an average follow-up time of 28.1±10.1 months. The follow-up rate was 89%. However, eight patients were lost to follow-up. During the follow-up, five patients succumbed to cardiovascular and cerebrovascular diseases, whilst the other 60 patients remained alive during the follow-up period.
A number of associated factors can affect the residual margin, including sex, age, lesion location, tumor diameter, depth of invasion, endoscopic treatment, EUS before resection, working experience of the endoscopist and degree of tumor differentiation (
Applications of EMR and ESD are becoming increasingly common for the treatment of early esophageal cancer (
After the endoscopic resection of early esophageal cancer, the positive rate of resection edge varies greatly according to the literature, ranging 1.7-22% (
Over recent years, an increasing number of gastroenterologists in China consider ESD to be the optimal choice for the treatment of early esophageal cancer (
Isomoto
Preoperative evaluation of the depth of tumor invasion can minimize the residual edge of deep resection (
The degree of tumor differentiation has also been previously established to be an independent risk factor (
It remains unclear whether surgery and other medical interventions should be actively performed for patients with residual margins after endoscopic resection. For the designation of subsequent treatment plans, the patient's age, complications and willingness should also be considered. In this group of data, amongst the nine patients with positive deep margins, six patients received surgical treatment, two patients received radiotherapy and chemotherapy, whereas one patient was closely observed. No recurrence was found during the follow-up. Among the 64 patients with positive lateral margins, one patient received radiotherapy, one patient received chemotherapy, six patients received surgical treatment, 20 patients received additional EMR or ESD, eight patients were lost to follow-up and the remaining 28 patients were closely observed. During the follow-up period, five patients succumbed to cardiovascular and cerebrovascular diseases whereas no recurrence was found in other patients. In the present study, a preliminary prognostic analysis of patients with positive margins after endoscopic resection of early esophageal cancer was performed. A more detailed prognostic analysis needs to be verified by a multicenter study with a longer term of follow-up.
The present study has a number of limitations. The present study is only a retrospective single-center study, not a randomized controlled study. Only one pathologist participated in the analysis of the tissues. Therefore, there may be potential selection bias in the present study. Prospective clinical trials may be conducted in the future to further verify these results.
In conclusion, the present study analyzed the risk factors associated with the residual margin and the prognosis of patients. According to the results of data analysis, it is highly recommended to apply EUS for evaluating the depth of tumor invasion, determining the depth of lesion invasion and the indication of endoscopic resection before operation, all of which can effectively prevent a residual margin. If biopsy indicates a poorly differentiated tumor, more aggressive treatment strategies may be required to prevent recurrence after endoscopic resection.
Not applicable.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
YF and BQL designed the study. YF and SG confirm the authenticity of all the raw data. YF and WW collected clinical and pathological data of patients. SG and YF analyzed the data. BQL and WW contributed to the interpretation of results. All authors critically reviewed the manuscript, and read and approved the final manuscript.
All patients and their families agreed to participate in the present study and signed an informed consent form. The study was approved by the Ethics Committee of the Fourth Hospital of Hebei Medical University (Shijiazhuang, China).
Not applicable.
The authors declare that they have no competing interests.
Endoscopic resection procedure for early esophageal squamous cell cancer. (A) Upper gastrointestinal endoscopy revealed a lesion located at the middle esophagus (the lesion is indicated by arrows). (B) Upper gastrointestinal endoscopy image of the esophagus after endoscopic resection. (C) En bloc image of the resected specimen, 6x4 cm (the lesion was indicated by arrows). (D) High-grade intraepithelial neoplasia in the deep resection margin as shown by H&E staining. The lesion was indicated by arrows. Magnification, x200.
Comparison of the groups with and without post-endoscopic resection residues at resection margins.
Parameter | Residues at resection margin (n=73) | No Residues at resection margin (n=308) | P-value |
---|---|---|---|
Age (years) | 64.8±8.9 | 60.9±11.4 | 0.891 |
Sex | 0.435 | ||
Female | 23 | 112 | |
Male | 50 | 196 | |
Location | 0.136 | ||
Upper | 3 | 23 | |
Middle | 42 | 201 | |
Lower | 28 | 84 | |
Tumor diameter | <0.001 | ||
≤1 cm | 2 | 29 | |
1.1-3 cm | 28 | 190 | |
>3 cm | 43 | 89 | |
Endoscopic treatment methods | 0.03 | ||
Endoscopic mucosal resection | 25 | 68 | |
Endoscopic submucosal dissection | 48 | 240 | |
Endoscopic ultrasonography evaluation before resection | <0.001 | ||
Yes | 42 | 257 | |
No | 31 | 51 | |
Working experience | 0.673 | ||
≥5 years | 45 | 198 | |
<5 years | 28 | 110 | |
Depth of invasion | <0.001 | ||
Intramucosal cancer (M1) | 30 | 208 | |
Lamina propria (M2) | 11 | 33 | |
Muscularis mucosa (M3) | 9 | 45 | |
Shallow and deep submucosal layer (SM1-2) | 23 | 22 | |
Differentiation | <0.001 | ||
Well | 23 | 233 | |
Moderate | 29 | 52 | |
Poor | 21 | 23 |
Results of multivariate logistic regression analysis.
Parameter | P-value | Odds ratio | 95% Confidence interval |
---|---|---|---|
Age | 0.820 | 1.051 | 0.686-1.610 |
Sex | 0.437 | 0.763 | 0.385-1.510 |
Maximum diameter of resected specimen | 0.39 | 1.325 | 0.698-2.515 |
Location | 0.663 | 1.187 | 0.549-2.564 |
Endoscopic resection procedures | 0.526 | 0.774 | 0.350-1.710 |
Depth of tumor invasion | <0.001 | 2.182 | 1.704-2.795 |
Work experience | 0.155 | 0.624 | 0.325-1.196 |
Degree of tumor differentiation | 0.018 | 0.451 | 0.166-1.224 |
Endoscopic ultrasonography before resection | <0.001 | 35.826 | 7.400-173.454 |